RNA-dependent RNA polymerase positive strand RNA viruses make up a large superfamily of viruses from many distinct subfamilies. These viruses span both the plant and animal kingdoms causing pathologies ranging from mild phenotypes to severe debilitating disease. The composition of the positive strand RNA virus polymerase supergroup is as follows. I. Picorna- (HAV, polio, Coxsackie), noda-, como-, nepo-, poty-, bymo-, sobemoviruses, and luteoviruses (yellows, yellow drawf, and leafroll virus). II. Carmo-, tombus-, dianthoviruses, pestiviruses, toga-, echo-, Dengue, hepatitis C virus, flaviviruses. III. Tobamo-, tobra-, hordei-, tricoma-, alpha, rubi-, furoviruses, hepatitis E virus, potex-, carla-, tymoviruses, and apple chlorotic leaf spot virus. The genomes of positive-strand RNA viruses encode RNA-dependent RNA polymerases which is the only viral protein containing motifs conserved across this class of viruses. This conservation is significant since this class of viruses contains significant phylogenetic variability, one would predict there are many ways in which the viruses infect cells and maintain stable replication. Besides the many differences, all the viruses in this class depend on a single fundamental step of RNA dependent positive strand RNA transcription. Since this step is essential for the viral life cycle this virus uses many host proteins to start and maintain RNA dependent RNA polymerase activity. Without the interaction of host factors the viruses would be unable to survive. Therefore a possible therapeutic intervention for inhibiting viral infection would be blocking the virus host interaction. If host factors essential for the virus but not essential for the host can be manipulated, then the ability to block viral infection could be achieved. Targeting host proteins has already been proven to be an efficacious approach to disrupt viral infection and replication for HIV, HCV, small pox, etc.
The significance of positive strand RNA viruses is the impact on human health and viability. Several positive strand RNA viruses infect humans and in many cases lead to debilitating disease and/or morbidity. Several viruses with a particular burden on human health is the Dengue virus (hemoragic fever), HCV (chronic liver disease, liver failure, fibrosis, and cancer), and HEV (fulminant hepatic failure). The liver and blood diseases caused by these viruses causes millions of deaths world wide and costs the heath care industry billions of dollars in liver related illness. The significance of finding therapies for curbing viral infection is great and would improve human health around the world.
As such there exists an unmet need for effective treatment of infections caused by HCV and other positive strand RNA viruses (listed above).
This specification also relates to double-stranded RNA molecules (dsRNA). dsRNA have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) discloses the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in C. elegans. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr. Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.). This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene.
PCT Publications WO 2003016572, WO 2003070750 and WO 2005028650 disclose previous efforts to develop nucleic acid based RNAi medicaments for the treatment of disease caused by HCV infection. PCT Publication WO2006074346 discloses previous efforts to treat RSV infection using RNAi medicaments.
Despite significant advances in the field of RNAi and advances in the treatment of pathological processes mediated by viral infection, there remains a need for agents that can inhibit the progression of viral infection and that can treat diseases associated with viral infection. The instant invention discloses compounds, compositions and methods that meet this need, and provide other benefits as well.